The levels of the NMDA receptor co-agonist D-serine are reduced in the substantia nigra of MPTP-lesioned macaques and in the cerebrospinal fluid of Parkinson's disease patients.

Abstract

Dysfunction of NMDA receptor (NMDAR)-mediated transmission is supposed to contribute to the motor and non-motor symptoms of Parkinson's Disease (PD), and to L-DOPA-induced dyskinesia. Besides the main agonist L-glutamate, two other amino acids in the atypical D-configuration, D-serine and D-aspartate, activate NMDARs. In the present work, we investigated the effect of dopamine depletion on D-amino acids metabolism in the brain of MPTP-lesioned Macaca mulatta, and in the serum and cerebrospinal fluid of PD patients. We found that MPTP treatment increases D-aspartate and D-serine in the monkey putamen while L-DOPA rescues both D-amino acids levels. Conversely, dopaminergic denervation is associated with selective D-serine reduction in the substantia nigra. Such decrease suggests that the beneficial effect of D-serine adjuvant therapy previously reported in PD patients may derive from the normalization of endogenous D-serine levels and consequent improvement of nigrostriatal hypoglutamatergic transmission at glycine binding site. We also found reduced D-serine concentration in the cerebrospinal fluid of L-DOPA-free PD patients. These results further confirm the existence of deep interaction between dopaminergic and glutamatergic neurotransmission in PD and disclose a possible direct influence of D-amino acids variations in the changes of NMDAR transmission occurring under dopamine denervation and L-DOPA therapy.

• Authors: Tommaso Nuzzo, Daniela Punzo, Paola Devoto, Elena Rosini, Silvia Paciotti, Silvia Sacchi, Qin Li, Marie-Laure Thiolat, Celine Véga, Massimo Carella, Manolo Carta, Fabrizio Gardoni, Paolo Calabresi, Loredano Pollegioni, Erwan Bezard, Lucilla Parnetti, Francesco Errico, Alessandro Usiello
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 8898 (06 20 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31222058 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, N-Methyl-D-Aspartate
• Serine

Topics

• Animals
• Humans
• MPTP Poisoning (metabolism)
• Macaca
• Mice
• Parkinson Disease (cerebrospinal fluid)
• Receptors, N-Methyl-D-Aspartate (agonists)
• Serine (metabolism)
• Substantia Nigra (metabolism)